Patients with type 2 diabetes mellitus (T2DM) have accelerated vascular aging and premature cardiovascular disease. There is a critical need for therapies to reduce cardiovascular events in T2DM. Recent trials with glucose lowering therapies, including GLP-1 agonists and SGLT2 inhibitors, demonstrate cardiovascular benefit but the mechanisms of vascular protection remain incompletely understood. Alterations in endothelial function, driven by inflammation and lower nitric oxide production, promote atherosclerosis in T2DM. Using an innovative methodology to study endothelial cells from patients with T2DM, we have identified signaling pathways that contribute to endothelial dysfunction and are reversible with novel agents including the GLP-1 agonist, liraglutide. Studies from animal models support the relevance of non-coding (nc) RNAs including microRNA and long noncoding (lnc) RNAs to endothelial inflammation, senescence and oxidative stress. In human T2DM, there is a paucity of information regarding endothelial ncRNA and altered cell signaling due to the challenges of obtaining human vascular tissue. Our model of isolated patient endothelial cells is a powerful strategy to assess pharmacotherapies and targets including ncRNAs. We hypothesize that ncRNAs (along with Basic Project) and biomarker-identified signaling pathways (along with Clinical Project) will play a functional role in endothelial cells from patients with T2DM and that treatment with GLP-1 agonists or SGLT2 inhibitors will restore endothelial and vascular function. We propose a cross-sectional study of 200 patients (100 with T2DM and 100 controls) and a 6-week randomized study of liraglutide or dapagliflozin or placebo (20/group) in 60 patients with T2DM to complete the following aims: 1. To identify and validate the relevance to vascular health of ncRNA in endothelial cells from patients with T2DM with and without atherosclerotic cardiovascular disease; 2. To assess the functional relevance of ncRNAs, biomarker-identified signaling pathways, and T2DM treatments (liraglutide and dapagliflozin) in patient endothelial cells; and 3. To determine whether T2DM treatments will restore endothelial health (ncRNA, NO production, inflammation) along with vascular health (vasodilator function, arterial stiffness). These studies will provide information regarding the contribution of ncRNA to vascular dysfunction and have the potential to generate novel therapies to restore vascular health in T2DM.
|Program type||Strategically Focused Research Network|
|Effective start/end date||01/01/2020 → 12/31/2023|